Screening for Small-Molecule Agonists for GPCRs Implicated in Narcolepsy and Schizophrenia

Mentors: Raj Rajendran

This summer, Alexxa studied three different G-Protein Coupled Receptor proteins: orexin receptor type 1 (OX1R) and type 2 (OX2R) and GPR85. Lower levels of orexin A and B (the ligands for OX1R and OX2R) lead to narcolepsy in humans, dogs, and rodents. Thus, finding an agonist for the orexin receptors could be an ideal substitute for patients with low levels of the orexin ligand. Higher levels of GPR85 are shown to cause low brain weight and other symptoms of psychiatric disorders, most notably schizophrenia. However, the ligand for this receptor is not known.

Alexxa and her mentor performed chemical screens to find small molecule agonists for the orexin receptors, and small molecule ligands for the GPR85 receptor. They screened 4160 chemical compounds, but no hits in the screen for ligands of GPR85 were identified. In contrast, they identified 9 hit compounds for OX1R, and 12 hit compounds for OX2R, each of which increased the activity of the receptor.



Alexxa, a senior at Boston Latin School, searched for chemical compounds that interact with receptor proteins implicated in narcolepsy and schizophrenia.